With the expansion of the rubber industry and the industrial revolution, exploration for rubber reached the area briging colonizers that altered and in some cases extinguished the majority of the indigenous population.

The territory was first made into a territorial division in 1910 and functioned as Commissaries (Comisarias) with the town of Calamar as capital (located in present-day Guaviare) but later moved to the town of Mitú to make an "act of presence" near the border with Brasil. In 1963 Guainía segregated from the Vaupes and became a commissary. In 1977, Guaviare followed the same path.

Because of its location in the Amazon jungle, it has no roads connecting it with the rest of the country or internally from settlement to settlement, and commerce and contact with the outside world is achieved through travel along the main rivers and by means of air travel. Several of the small settlements have airstrips with service to the department's capital, Mitú, and from there with the rest of the country.[6]

Because of its small population and vast extension of land, Vaupés only has 3 municipalities. Other sections of the Department were classified as an especial type of Corregimiento, which has certain hybrid functions from a municipality and corregimiento.